New discoveries about animal viruses that can infect humans

In a new study, scientists have identified a protein in mammals that welcomes arteriviruses into host cells, initiating infection. The team also found that an existing monoclonal antibody that binds to this protein protects cells against viral infection.

Arteriviruses are common in many types of mammals around the world that serve as natural hosts – such as non-human primates, pigs and horses – but have not yet been detected in humans.

The researchers’ goal is to better understand the mechanisms of arterivirus infection to determine how high the risk of infection is in humans and what preparations may be needed if the virus is transmitted in the future.

“It’s important to consider that since we don’t know the arteriviruses that infect humans, we are essentially immunologically naive, so we can’t rely on pre-existing immunity to help us,” said co-author Cody Warren, assistant professor of veterinary biological sciences at The Ohio State University .

Warren collaborated with Adam Bailey, assistant professor of pathology and laboratory medicine at the University of Wisconsin-Madison. The study was recently published in Nature communication.

Many natural hosts of arteriviruses show no symptoms of disease, but the virus infecting pigs can cause pneumonia as well as abortions in pregnant pigs, and other strains can cause hemorrhagic fever or encephalitis when switching animal hosts.

These viruses also have a remarkable ability to maintain long-term infections and become more virulent when they find new hosts – giving them time to evolve and increase their chances of transmission.

The research team set out to find proteins in mammals that arteriviruses use as receptors to enter host cells and make copies of themselves. Bailey used genome-wide CRISPR knockout screening technology to identify specific genes whose disruption causes cells to become resistant to viral infection. Such genes could then be considered essential for the viral infection process. The unbiased screen identified two genes, FCGRT AND B2Mwhose protein products combine to form the FcRn receptor (neonatal Fc receptor), which is expressed on the surface of cells.

The FcRn receptor molecule plays a specific role in transporting antibodies across the placenta to the fetus, but it is also present in immune cells and cells lining the walls of blood vessels – both of which are targets of arteriviruses.

The results of this study demonstrated that FcRn is used for host cell entry by at least five arteriviruses infecting monkeys, pigs, and horses, respectively: three different strains of simian arteriviruses, porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), and equine rhinitis virus arteries (EAV).

Knockout of the main component of the FcRn complex – the so-called FCGRT gene – from host cells blocked viral infection, and pretreatment of cells with a monoclonal antibody against FcRn protected against infection.

There was also a genetic twist to this story: some mammalian hosts were less susceptible to arterivirus infection due to differences in their species-specific FcRn sequence, meaning that in some cases this protein would act as a barrier to cross-species infections.

“Chimpanzees and humans have almost the same genes, but the sequence of those genes is slightly different,” Bailey said. “All mammals have the FcRn receptor, but their ability to maintain infection with a given arterivirus may vary.”

The CRISPR screen also identified a gene encoding another surface protein, CD163, which Warren and colleagues previously discovered as a gatekeeper for an arterivirus called simian hemorrhagic fever virus (SHFV) to infect cells.

A series of experiments on different cell types and the use of multiple virus strains in the new study showed that CD163 does play a role in infection with most arteriviruses, but cannot act on its own – interaction with FcRn is also key to facilitating arteriviral infection of host cells.

Scientists say defining the stages of arterivirus infection is an important milestone.

“If we look at the biology of the virus, one of the most important things we can understand is the mechanisms of entry. Because if you can stop the virus’s ability to infect a cell by interrupting the initial contact of the virus with the receptor, now you have a potential therapeutic strategy,” Warren said.

One of these “disruptors” can block the receptor, so demonstrating that an existing monoclonal antibody can stop a viral infection in cells is also an advantage for scientists studying viruses through the lens of pandemic preparedness.

“I think if one of these viruses showed up in humans, we would be in real trouble,” Bailey said. “That’s motivation for me.”

This work was supported by grants from the National Institutes of Health, University of Wisconsin-Madison Startup Funds, the G. Harold and Leila Y. Mathers Foundation, and the Burroughs Wellcome Fund’s Pathogenesis of Infectious Disease Program.

Co-authors included Teressa Shaw, Kylie Nennig, Xueer Qiu, Devon Klipsic and Igor Slukvin of UW-Madison; Ohio State’s Devra Huey, Makky Mousa-Makky, Jared Compaleo, Fei Jiang and Haichang Li; Aadit Shah of Stanford University; Raymond Rowland of the University of Illinois at Urbana-Champaign; and Meagan Sullender and Megan Baldridge of Washington University in St. Louis.